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CEP > Week 8 > Flashcards

Week 8 Flashcards

1
Q

Functions of the skeleton

A

Mechanical- support and muscle attachment
Protective- for vital organs and marrow
Metabolic- ion homeostasis especially calcium and phosphate

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2
Q

Basic structure of bones

A

Epiphysis- end part of long bone, initially growing separately form shaft
Diaphysis- shaft or central part of long bone
Metaphysis- wide portion of long bone and regions of bone where growth occurs
Cortical bone- dense and solid and surrounds marrow space (compact, lamellar)
Cancellous (trabecular) bone- bone involved in bone turnover
Articular cartilage
Growth (epiphysial) plate

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3
Q

What is bone made of

A

Specialised connective tissue
Extracellular matrix which is able to calcify
Collagen fibres
Non collagenous proteins essential to bone function (osteocalcin, osteonectin, osteopontin)
Mineralisation (calcification) occurs with formation of hydroxyapatite crystals (complex of calcium and phosphate crystals). Embedded in bone to give bone structural integrity
Contains several types of cells

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4
Q

Cell types within bone

A

Osteocytes
Osteoblasts
Osteoclasts

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5
Q

Osteocytes

A

Deep embedded in calcified bone matrix, have long processes which contact other osteocytes and osteoblasts. Important for regulation of bone turnover

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6
Q

Osteoblasts

A

Bone forming cells which produce matrix constituents and aid calcification. Collagen and hydroxyapatite
Originate from mesenchymal stem cells (bone marrow stem cells or connective tissue mesenchymal cells)
Classical marker- alkaline phosphatase (regulator of bone mineralisation), osteocalcin (non-collagenous protein)

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7
Q

Osteoclasts

A

Bone resorbing cells usually found in contact with calcified bone surface- in lacunae
Multinucleated- originate from bone marrow lineage
Produce acid (to resorb mineral) and enzymes (to resorb matrix)
Attachment to bone very important- integrins
Classical markers- carbonic anhydrase, tartrate-resistant acid phosphatase (TRAP), RANK, calcitonin receptor

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8
Q

What is an osteoid

A

Unmineralised bone tissue

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9
Q

Osteoclasts development

A

Osteoblast contain RANK ligand (RANKL) and attaches to RANK receptor on osteoclast precursor. Regulated by VIT D, PTH
Then forms a mature osteoclast
Osteoprotegerin OPG, interacts with RANK ligand and prevent osteoclast interaction. Regulated by estrogens
Denosumab- limits production of mature osteoclast by acting as a decoy for RANK ligand receptor process

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10
Q

Bone cells and bone remodelling

A

Dynamic process
Osteoclast binds to bone surface (integrens)
Resorption
Osteoclast releases acid and enzymes forming resorption pit. Releasing Ca2+/PO4 +collagen
Forms osteoid
Layers of collagen mineralised to form new bone by osteoblasts

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11
Q

The bone remodelling cycle (trabecular bone)

A

Resting surface
Osteoclast, bone resorption
Osteoblast, reversal phase
Bone formation (osteoid)
Bone formation (osteoid- mineralisation front)
Resting surface
Hope that same amount bone produced as bone resorbed

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12
Q

Osteoporosis

A

Loss of bone mass (increased risk of fracture)
Increase in bone mass as age increases, reach peak bone mass at 20-30
Osteoblasts dominating osteoclasts, more bone mass
As you get older process reverses osteoclast dominate, bone resorption dominates over formation, bone mass decreases

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13
Q

Bone and calcium homeostasis

A

Bone - protect vital organs, support muscles, reservoir of calcium. >99% calcium
Soluble calcium- excitable tissue, muscle contraction, nerves, cell adhesion <1%

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14
Q

Calcium homeostasis

A

GI tract, absorb Ca
Kidney, homeostatically controlling ca release
Bone

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15
Q

Parathyroid hormone PTH

A

84 amino acid peptide but biological activity in first 34 amino acids (PTH 1-34), half life 8 mins
Normal adult reference range =1.6-6.9 pmol/L
Binds to cell membrane G protein coupled receptors
Causes signalling inside cell. Mainly in kidney and osteoblasts

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16
Q

Hypocalcaemia

A

Calcium sensitive receptors in parathyroid
Increased PTH secretion
Increase bone resorption,
Kidney: increase urinary phosphate, decrease urinary calcium, increase 1,25D3 production (active from vitD)
Intestine: increase calcium and phosphate absorption
Increase serum calcium
Negative feedback mechanism

17
Q

Vitamin D

A

Best used to refer to precursor form 25-hydroxyvitamin D3 (25D3)
Numbers after name reflect origin, Vit D2 of plant origin, Vit D3 of animal origin
Numbers before name reflect changes (hydroxylations) in Vit D that change its biological activity (1,25D3) binds to intracellular vitamin D receptor VDR, active from of vit D made in kidneys
25D3 is easier and cheaper to measure so used most in hospitals
<50nmol/L [20ng/ml] is insufficient

18
Q

Where do we get vit D from

A

UV radiation mainly - skin (7-dehydrocholesterol)- Vit d3
Diet—vitamin D3
Into blood , into liver (25D3), into kidney which activates 25D3, stimulated by PTH to produce 1,25D3

19
Q

Calcitonin

A

Produced by thyroid c-cells (parafollicular- which dont produce thyroid hormones)
Calcitonin released in hypercalcaemia, inhibits bone resorption (by direct effect on osteoclasts), no ca released
Not essential to life

20
Q

Hypercalcaemia

A

Thyroid increases calcitonin production, decreases bone resorption
Kidney: decrease urinary phos, increase urinary calcium, decreased 1,25D3 production
Intestine: decrease calcium and phosphate absorption
Decrease serum calcium

21
Q

Fibroblast growth factor 23 (FGF23)

A

Phosphate regulating hormone
Produced by bone cells (osteocytes and maybe osteoblasts)
Released in response to high serum PO4
Increase renal excretion of PO4 and suppresses renal synthesis of active vit D
Main inducer of FGF23 appears to be 1,25D3

22
Q

Hyperphosphataemia

A

Osteocytes sense change and produce more FGF23
Increase FGF23 in bone, suppresses 1,25D3
Kidney: increase in urinary phos, decrease urinary calcium
Dominant effects on kidney reverses high phosphate
Decreasing serum phosphate

23
Q

Primary hyperparathyroidism

A

Raised serum PTH:
Parathyroid tumour (usually benign adenoma)
Causes hypercalcaemia and low serum phosphate
Loss of negative feedback. Treatment is surgery, can be given calcimimetics
Clinical features: lethargy/confusion, thirst/polyuria, renal stones, constipation, pancreatitis, joint pain, fracture, depression, hypertension

24
Q

Calcimimetics

A

Drugs that are allosteric activators of calcium sensing receptor. So enhancing signalling and decreasing PTH release

25
Q

Rickets/ osteomalacia

A

Deficiency of VIT D
Lack of mineralisation of collagen component of bone (osteoid) , failure to absorb sufficient calcium from GI tract
Called rickets when affecting growing skeleton, osteomalacia when affects adult
Dietary/lack of sunlight, rarely inherited (mutations in VIT D receptor, 1-alphahydroxylase defects (enzyme that produces active vit d), x-linked hypophosphataemic rickets)
Treatment vit D replacement

26
Q

Rickets symptoms

A

Osteoid at growth plate is weak (bow legs). Growth plate is where bones developed , area of tissue near ends of long bones in children and teens, determine future length and shape of mature bone
Growth plate expands to compensate (swollen joints)

27
Q

Osteomalacia symptoms

A

Bone pain, pseudofractures

28
Q

Rickets and osteomalacia leads to hypocalcaemia

A

Since not enough vit D, so not enough 25D3, therefore there’s not enough substrate for the enzyme in the kidney so not enough 1,25D3 formed
Body cant absorb enough minerals
Decreasing serum calcium more

29
Q

Secondary hyperparathyroidism

A

Secondary to renal disease
Increased serum phosphate, decreased activation of vit D to 1,25D3, kidneys not working
Treatment with phosphate binders or vit D analogues (synthetic forms of active form of VIT D)
FGF23 trying to prevent hyperphosphataemia
Lower serum calcium
Decreased absorption of ca and phos
Ca and 1,25D3 low leads to osteomalacia
Phosphate and calcium disorder

30
Q

Oncogenous osteomalacia

A

High serum FGF23 and low serum 1,25D3 due to benign tumour secreting FGF23
Ricket like phenotype

31
Q

X-linked hypophosphaemic rickets

A

PHEX protein targets FGF23. Mutations in the PHEX gene lead to elevated FGF23 and suppressed 1,25D

32
Q

Osteoporosis

A

Loss of bone mass/density= both mineral and non mineral bone decreased
Leads to increased fracture risk, wrist, spine, hip
Osteoporosis of aging
Postmenopausal osteoporosis= rapid decline in female bone density following decline in oestrogen
Steroid-induced osteoporosis= decline in bone density associated with use of steroids as therapy for inflammatory disease

33
Q

Spinal osteoporosis

A

Compression fractures from vertebrae collapsing on themselves
Kyphotic spine
Kyphosis is curvature of spine causing top to be more rounded

34
Q

Osteoporosis therapeutic options

A

Hormone replacement therapy- oestrogen, as oestrogen deficiency increases bone remodelling and bone resorption
Inhibition of osteoclast development- denosumab (RANK ligand antibody), blocks ligand on osteoblasts from interacting with osteoclasts, decreased differentiation of pre-osteoclasts
Inhibition of osteoclast activity- bisphosphonates, disrupt intracellular enzymes required for osteoclast activity
Stimulation of osteoblast activity (anabolic)- use of PTH stimulates osteoblasts>osteoclast. Teriparatide. Stimulates bone formation

35
Q

Osteoporosis prevention options

A

Diagnosis of osteoporosis risk is made based on assessment of low bone mineral density BMD using DEXA or ultrasound and lab investigations. Optimal BMD may prevent osteoporotic fracture
Exercise may enhance osteocyte activity through bone stress
Vit D and calcium could help maintain general bone health
Avoid smoking and high levels of alcohol intake

36
Q

What is tetany

A

Symptom that involves involuntary muscle contractions and overly stimulated peripheral nerves
Often caused by electrolyte imbalance most often low calcium levels

37
Q

Symptom if you remove parathyroid glands

A

Tetany

CEP (10 decks)

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